Discontinuation Of Bisphosphonate Therapy Research Articles

Progression of atypical femur stress fracture after discontinuation of bisphosphonate therapy

Atypical femur fracture (AFF) is an uncommon complication of long-term bisphosphonate use, but the risk declines substantially after treatment cessation. We report a case of a 70-year-old woman with osteopenia treated with alendronate for 9 years who presented with right mid-thigh pain and radiographic findings of focal lateral cortical thickening in the right mid-femur and lateral cortex irregularity in the proximal-mid left femur. Alendronate was discontinued, but she remained on estrogen for menopausal symptoms. Four years later, a horizontal linear translucent defect was seen in the right mid-femur area of cortical hypertrophy, consistent with an incomplete AFF. The patient underwent prophylactic intramedullary rodding of the right femur and estrogen was discontinued. Three years later (7 years after initial presentation), the cortical irregularities in the left femur were more prominent and three small horizontal linear translucent defects were now evident, consistent with early incomplete atypical fracture development. The patient also suffered a wrist fracture. She was treated with teriparatide for 1.5 years with resolution of the translucent defects in the left but not the right femur, although abnormal thickening of the lateral cortex persisted in both femurs. Our case demonstrates incomplete atypical femur fracture progression in a patient with long-term bisphosphonate exposure, even after treatment cessation. These findings highlight the importance of follow-up for patients who develop diaphyseal femur stress fractures and the potential for early healing with anabolic therapy. This case also demonstrates the challenge in managing older patients with incomplete AFF at risk for progression to complete AFF and osteoporotic fracture.

MON-510 Progression of Atypical Femur Stress Fracture after Discontinuation of Bisphosphonate Therapy

Background: The risk of bisphosphonate (BP)-induced atypical femur fracture (AFF) is believed to be markedly reduced following BP discontinuation. In this case, we report development and worsening of incomplete AFF occurring years after BP was discontinued. Clinical Case: A 70-year old woman with osteopenia presented with atraumatic, unilateral, right mid-thigh pain (dull, achy, worse with weight-bearing). Prior and current prescription medications included alendronate (over 8 years duration), estrogen for menopausal symptoms, levothyroxine and antihypertensive medications. Initial X-ray of the right femur revealed focal thickening of the lateral mid-shaft femoral cortex. Radionuclide bone scan demonstrated focal scintigraphic uptake consistent with stress fracture at that site and also contralateral uptake in the left subtrochanteric region. X-ray of the left femur showed thickening of the lateral cortex extending to the subtrochanteric region, but more extensive and slightly irregular thickening of the mid-femur lateral cortex. Urine N-telopeptide was 17 nmol BCE/mmol creatinine and osteocalcin was 8.4 ng/mL. Alendronate was discontinued but estrogen was continued due to ongoing menopausal symptoms. One year later, the irregular thickening of the left lateral cortex was noted to be more prominent. Urine N-telopeptide was 15 nmol BCE/mmol creatinine and osteocalcin was 12 ng/mL. Four years after initial presentation, a right horizontal linear translucent defect (dreaded black line) became evident within the area of cortical hypertrophy, thus, meeting radiographic criteria for AFF. Because of these findings, the patient underwent prophylactic intramedullary rodding of the right femur and estrogen was discontinued. Over the ensuing 3 years (total of 7 years after initial presentation), x-ray showed progression of the irregular cortical thickening in the left femur, with development of 3 focal areas of lateral cortical protuberance, each showing a horizontal linear translucent line. The patient was started on teriparatide for 1 year, with subsequent imaging showing resolution of the translucent defects, but persistence of pronounced abnormal cortical thickening. Conclusion: Our case illustrates the importance of long-term follow-up in patients who have complete or partial AFF. Monitoring is particularly important in cases with extensive and irregular cortical thickening, since partial AFF can progress and worsen even years after discontinuation of BP and other antiresorptive medications. In such cases, teriparatide may be a treatment option to enhance bone turnover, thus allowing improvement in bone repair mechanisms.

Fracture prediction after discontinuation of 4 to 5 years of alendronate therapy: the FLEX study.

Discontinuation of bisphosphonate therapy after 3 to 5 years is increasingly considered, but methods to monitor fracture risk after discontinuation have not been established. To test methods of predicting fracture risk among women who have discontinued alendronate therapy after 4 to 5 years. The prospective Fracture Intervention Trial Long-term Extension (FLEX) study randomized postmenopausal women aged 61 to 86 years previously treated with 4 to 5 years of alendronate therapy to 5 more years of alendronate or placebo from 1998 through 2003; the present analysis includes only the placebo group. Hip and spine dual-energy x-ray absorptiometry (DXA) were measured when placebo was begun (FLEX baseline) and after 1 to 3 years of follow-up. Two biochemical markers of bone turnover, urinary type 1 collagen cross-linked N-telopeptide (NTX) and serum bone-specific alkaline phosphatase (BAP), were measured at FLEX baseline and after 1 and 3 years. Symptomatic spine and nonspine fractures occurring after the follow-up measurement of DXA or bone turnover. During 5 years of placebo, 94 of 437 women (22%) experienced 1 or more symptomatic fractures; 82 had fractures after 1 year. One-year changes in hip DXA, NTX, and BAP were not related to subsequent fracture risk, but older age and lower hip DXA at time of discontinuation were significantly related to increased fracture risk (lowest tertile of baseline femoral neck DXA vs other 2 tertiles relative hazard ratio, 2.17 [95% CI, 1.38-3.41]; total hip DXA relative hazard ratio, 1.87 [95% CI, 1.20-2.92]). Among postmenopausal women who discontinue alendronate therapy after 4 to 5 years, age and hip BMD at discontinuation predict clinical fractures during the subsequent 5 years. Follow-up measurements of DXA 1 year after discontinuation and of BAP or NTX 1 to 2 years after discontinuation are not associated with fracture risk and cannot be recommended. clinicaltrials.gov Identifier: NCT00398931.

Reviews of Current Literature

Malden N, Lopes V. An epidemiological study of alendronate-related osteonecrosis of the jaws. A case series from the south-east of Scotland with attention given to case definition and prevalence. J Bone Miner Metab. 2011. [Epub ahead of print[This article presents a close case study series of alendronate-associated osteonecrosis of the jaws (AONJ). From their study the authors draw epidemiologic conclusion regarding AONJ as well as comment on clinical considerations and treatment protocol. Alendronate is the most common bisphosphonate prescribed in the world. Since the first cases of ONJ started to emerge a task force of the American Society of Bone and Mineral Research (ASBMR) proposed recommendations to address key issues with ONJ and bisphosphonates. These include case definition and clinical management as well as epidemiology. In this study, to confirm and stage AONJ, the authors used the definition proposed by American Association of Oral and Maxillofacial Surgeons 2009 position papers on BONJ. The specific details for case definition, as described by ASBMR, fall in to 7 categories of information (A–G): A, patient details—for this article all were white Caucasian except for one, and 82% were female; B, diagnosis/staging of disease—mild to moderate pain, presence of nonvital bone; C, local site and clinical history—64% included a history of dental extraction preceding the condition; D, alendronate dose and duration of presentation—70 mg daily dose; the duration of administration to first ONJ recognition had a mean of 3 years; E, indication for bisphosphonate use—64% were receiving alendronate to counteract the osteoporotic affects of glucocorticosteroids; 36% were receiving the drug for age-related or hormone/menopause-related osteoporosis; an estimate mean of 4.7 years of “disease onset” prior to ONJ onset; F, co-morbidity and duration of ONJ—55% were ASA III; duration of comorbidity to diagnosis of ONJ was difficult to assess, but in 64% it was considered between 5 and 10 years; G, co-medications and duration of ONJ—prednisolone was prescribed in 55% of the cases. Three patients were taking immunosuppressant leflunomide or methotrexate. A known complication of immunosuppressive drugs is oral ulcerations and 27% of patients had concomitant administration of those with alendronate. Four patients with cardiovascular disease were taking statins and two were taking nicorandil. Nicorandil is a drug used in the management of persistent angina pectoris. It has been associated with oral ulcerations, occasionally affecting the alveolar ridges. Thus the authors suggest that drug associated ulcerations, if occurring over bone in the presence of alendronate could initiate the development of ONJ. Thus these drugs should be considered risk factors. 55% of patients who developed ONJ were taking prednisolon and alendronate.Management of ONJ included mild analgesics (64%), antimicrobials in various combinations (73%) that ranged from 1 to 11 weeks, one surgical debridement (64%), chlorhexidine was prescribed to all patients, and 45% of patients discontinued alendronate use at the diagnosis of ONJ. It was decided that the risk associated with discontinuation of alendronate are less then the risks associated with continuation of alendronate. However a case-by-case review with multispecialist discussion is suggested when discontinuation of bisphosphonate therapy is considered as a treatment adjunct to management of AONJ. In this study the duration from diagnosis to resolution ranged from 2 weeks to 20 months (mean of 6.5 months). By tracking alendronate prescriptions the drug patient year (DPY) was calculated. Thus epidemiology could be approximated. In the population studied, the incidence of AONJ as a spontaneous event or in response to a traumatic oral insult is between 0.03% and 0.017% respectively. Where alendronate is prescribed alone or for age-related or hormone-related osteoporosis the prevalence is 0.004%. The presence of comorbidity where comedications are being prescribed with alendronate significantly increases the risk of developing AONJ. It is suggested that rheumatoid arthritis patients receiving alendronate, glucocorticosteroids, and often an immunosuppressant are at an increased risk of ONJ with an incidence of 0.1% of AONJ. This study of 11 patients and an extrapolation to a population of 900 000 with DPY calculations brings our attention to AONJ from another clinical perspective that should benefit our patients and our considerations in their care.

Biochemical markers of bone turnover in osteonecrosis of the jaw in patients with osteoporosis and advanced cancer involving the bone

Osteonecrosis of the jaw (ONJ) has been hypothesized to result in part from a relative "oversuppression" of normal physiologic bone remodeling at the jaw brought about by bisphosphonate therapy. Biochemical markers of bone turnover give readily measurable information on integrated systemic bone remodeling activity, as measured by blood and urine assays. The intra- and interassay variability of most currently available assays is less than 10%, although many biological factors can influence levels of bone turnover markers. Bone turnover markers may show a dynamic response to changes in clinical status for a given disease state. Elevated bone turnover on and off treatment appears to predict adverse clinical consequences in both osteoporosis and cancer. Bisphosphonates effectively decrease the level of the bone turnover markers with a pattern depending on the marker, the bisphosphonate, the dose regimen, and the disease. However, long-term (10-year) treatment with bisphosphonates for osteoporosis does not appear to result in a progressive decline in bone turnover, as measured by markers and bone histology. The effects of long-term (greater than 2 years) treatment with monthly intravenous bisphosphonates on bone turnover markers in cancer are unknown. Discontinuation of bisphosphonate therapy appears to allow a recovery of bone turnover, which is related to the bisphosphonate, the duration of therapy, and the disease being treated. At this time, data are limited with regard to the utility of bone turnover markers in assessing risk for ONJ and whether bone marker-directed bisphosphonate holidays would be useful in prevention or treatment of ONJ.

How Patients' Lack of Knowledge About Oral Bisphosphonates Can Interfere With Medical and Dental Care

Oral bisphosphonate use has been associated with a small risk of developing oral osteonecrosis that occurs spontaneously or after the patient has undergone dental surgery. The authors conducted a study to determine whether patients taking bisphosphonates had knowledge about the medical indication for the therapy and the duration of treatment, as well as whether they had been educated by their physicians about possible adverse reactions. From June 2008 through April 2009, people seeking routine care in a dental clinic and who were being treated with bisphosphonates were invited to participate in the study. The participants were asked questions involving knowledge about the medical indications related to their taking bisphosphonates, the duration of their therapy and whether they had been educated about possible adverse reactions. The authors interviewed 73 participants; 84 percent stated they knew why they were receiving bisphosphonate therapy. However, 80 percent said they were unsure about the duration of therapy, and 82 percent could not recall if they had been told about the risk of experiencing adverse reactions, including oral osteonecrosis, by their physicians. People taking bisphosphonates may be unfamiliar with the drug and its possible adverse oral side effects. Dentists should be prepared to educate patients about the risks of developing oral complications resulting from bisphosphonate use and the need for appropriate dental care. Questions regarding discontinuation of bisphosphonate therapy should be answered by the physician.

Outcomes of bisphosphonate-related osteonecrosis of the jaw—Importance of staging and management guidelines: A large single institutional update

20526 Background: Bisphosphonate (BP) therapy is indicated in the treatment of pts. with symptomatic bony disease secondary to myeloma, solid tumors and in the treatment of osteoporosis. We have previously reported our experience with BP related osteonecrosis of the jaw (ONJ) (J Oral Maxillofac Surg 2004;62:527–34). The reported incidence of this entity in patients receiving IV BP’s is approx. 1–10%. The purpose of our current report is to update our experience and report the clinical outcome of the osteonecrotic lesion, with particular emphasis to clinical stage and after following stage specific management guidelines that we have previously published (Hematology 2006; 356–360). Methods: We performed a retrospective analysis of pts. records that were diagnosed with ONJ at our institution. IRB approval was obtained for this study. Information regarding age, gender, indication for BP treatment, type of BP used, stage of ONJ at time of presentation, outcome of ONJ with appropriate therapy were recorded. Results: Two hundred and seven pts. with ONJ were identified at our institution. Males: n=52; Females: n=155. Underlying frequent diagnoses: Myeloma: n=71; breast ca: n=68; osteoporosis: n=42; prostate ca: n=11; others: n=13. Prior BP therapy included exposure to pamidronate: n=87; zoledronic acid: n=123; oral BP: n=41. Ninety four patients were serially followed for outcome data regarding clinical course of ONJ after cessation of BP therapy. Improvement in ONJ was noted: n=24 (26%), stable disease: n=52 (55%), worsening of ONJ: n=18 (19%). Their initial stage of ONJ was recorded as Stage 1: n=26 (28%), Stage 2: n=45 (48%), Stage 3: n=23 (24%). Outcome by stage: stage 1 pts: improvement 19%; stable disease 73%, worsening 8%; Stage 2 pts: improvement noted in 31%, stable disease 47%, worsening 22%; Stage 3 pts: improvement in 22%, stable disease 52%, worsening 26%. Conclusions: With early detection at a lower stage, and careful conservative management, the large majority (74–92%) of pts. presenting with ONJ will have stabilization or improvement in their clinical presentation after discontinuation of BP therapy. Close coordination of care between oncologists and dental colleagues may optimize treatment outcomes with this entity. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen, Novartis Novartis